Pulmonary macrophages attenuate hypoxic pulmonary vasoconstriction via β3 AR/iNOS pathway in rats exposed to chronic intermittent hypoxia

Hisashi Nagai, Ichiro Kuwahira, Daryl O Schwenke, Hirotsugu Tsuchimochi, Akina Nara, Sayoko Ogura, Takashi Sonobe, Tadakatsu Inagaki, Yutaka Fujii, Rutsuko Yamaguchi, Lisa Wingenfeld, Keiji Umetani, Tatsuo Shimosawa, Kenichi Yoshida, Koichi Uemura, James T Pearson, Mikiyasu Shirai

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Chronic intermittent hypoxia (IH) induces activation of the sympathoadrenal system, which plays a pivotal role in attenuating hypoxic pulmonary vasoconstriction (HPV) via central beta1-adrenergic receptors (AR) (brain) and peripheral beta2AR (pulmonary arteries). Prolonged hypercatecholemia has been shown to upregulate beta3AR. However, the relationship between IH and beta3AR in the modification of HPV is unknown. It has been observed that chronic stimulation of beta3AR upregulates inducible nitric oxide synthase (iNOS) in cardiomyocytes and that IH exposure causes expression of iNOS in RAW264.7 macrophages. iNOS has been shown to have the ability to dilate pulmonary vessels. Hence, we hypothesized that chronic IH activates beta3AR/iNOS signaling in pulmonary macrophages, leading to the promotion of NO secretion and attenuated HPV. Sprague-Dawley rats were exposed to IH (3-min periods of 4-21 O2) for 8 h/d for 6 weeks. The urinary catecholamine concentrations of IH rats were high compared with those of controls, indicating activation of the sympathoadrenal system following chronic IH. Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of pro-inflammatory pulmonary macrophages. In these macrophages, both beta3AR and iNOS were upregulated and stimulation of the beta3AR/iNOS pathway in vitro caused them to promote NO secretion. Furthermore, in vivo synchrotron radiation microangiography showed that HPV was significantly attenuated in IH rats and the attenuated HPV was fully restored by blockade of beta3AR/iNOS pathway or depletion of pulmonary macrophages. These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of beta3AR/iNOS signaling in chronic IH.
Original languageEnglish
Article numbere0131923
Number of pages20
JournalPLoS ONE
Issue number7
Publication statusPublished - 2015

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